Isoindolo {8 7,1,2,-hij{9 {0 quinolines)

ABSTRACT

Isoindolo(7,1,2-hij)quinolines are provided having the structure   WHEREIN R5 can be hydroxyl, halogen, substituted amino, alkoxy, acyloxy, aroyloxy, substituted amido, and amino-subsituted amido; and R6 is hydrogen; and R5 and R6 can be taken together to form O; X, Y, R1, R2, R3 and R4 are as defined below; and which are anit-inflammatory agents, central nervous system depressants, inhibitors of cyclic AMP phosphodiesterase and sun-screening agents.

United States Patent [191 Levine Oct. 7, 1975 l l ISOINDOLO [7,l,2,-HIJ]QUINOLINES] [75] Inventor: Seymour D. Levine, North Brunswick, NJ.

[73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ

221 Filed: Nov. 19, 1973 [2t] AppliN0.:4l7,l56

Related US. Application Data [62] Division of Ser. No 215,189, Jan 3,1972. Pat No.

OTHER PUBLICATIONS ACS News. Apr. 3. 1972, p. 18, from Chemical andEngineering News." Burger, Medicinal Chemistry, l963. p. 42, col. l,par. 4, lnterscience publishers.

Primary ExaminerDonald G. Daus Assistant ExaminerDavid E. WheelerAttorney, Agent. or FirmLawrence S. Levinson; Merle J. Smith; Donald J.Barrack [57] ABSTRACT lsoindolo[7,l,2-hij]quinolines are provided havingthe structure wherein R can be hydroxyl, halogen, substituted amino,alkoxy, acyloxy, aroyloxy substituted amido, and amino-subsituted amido;and R is hydrogen; and R and R can be taken together to form =0; X, Y,R, R R and R are as defined below; and which are amt-inflammatoryagents, central nervous system depressants. inhibitors of cyclic AMPphosphodiesterase and sun-screening agents,

7 Claims, No Drawings ISOINDOLO [7,l ,2,-HU] QUINOLINES) This is adivisional application of US. Pat. application Ser. No. 2l5,l89, filedJan. 3, 1972, now US. Pat. 3,819,624, issued June 25, 1974.

This invention relates to isoindolo[7,l,2-hij] quinolines having thestructure substituted amido and aminosubstituted amide; R is hydrogenand R and R can be taken together to form =0, and acid-addition saltsthereof where applicable.

R and R" may be the same or different and represent hydrogen, loweralkyl, aryl and alkenyl. Furthermore,

R and R" can be taken together with N to form a heterocyclic ring.

The term lower alkyl as employed herein includes both straight andbranched chain radicals of up to and including eight carbon atoms, forinstance, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-tri-methylpentyl and the like. The lower alkyl group can includesubstituents such as aryl, halo, hydroxyl, alkoxy, amino or substitutedamino.

The term halogen includes F, Cl, Br or I.

The term aryl" as employed herein includes monocyclic carbocyelic arylradicals, for instance, phenyl and substituted phenyl radicals, such aslower alkylor alkoxyphenyl (e.g., 0-, m-, or p-tolyl, ethylphenyl,butylphenyl and the like), di(lower alkylJphenyl (e.g.,2,4-dimethylphenyl, 3,5-dicthylphenyl, and the like, and correspondingalkoxy compounds), halophenyl (e.g., chlorophenyl, bromophcnyl,iodophenyl and fluorophenyl J, o, mor p-nitrophenyl, dinitrophenyl(e.g., 3,5-dinitrophenyl, 2,6dinitrophenyl, and the like), andtrinitrophenyl (cg, picryl), and aminophenyl, such asp-dimethylaminophenyl.

The acyl" or aryl portion of the aeyloxy" or aroyloxy group,respectively, is derived from a hydrocarbon carboxylic acid of less than12 carbon atoms, which may be exemplified by the lower alkanoic acids[e.g., formic, acetic, propionic, butyric, valeric, trimethyl acetic andcaproic acids), the lower alkenoic acids (e.g., acrylic, methacrylic,crotonic, 3-butenoic and senecioic acids), the monocyclicaryl-carboxylic acids (e.g., benzoic and toluic acids), the monocyclicaryllower alkanoic acids [e.g., phenacetic, B-phenylpropionic,a-phenylbutyric, and S-(pmethylphenyl)pentanoic acids], the cycloalkylcarbox- LII ylic acids (e.g., cyclobutane carboxylic acid, cyclopentanecarboxylic acid and cyclohexane carboxylic acid), the cycloalkenylcarboxylic acids (e.g., 2-cyclobutene carboxylic acid and 3-cyclopentenecarboxylic acid), the cyclopentene carboxylic acid), the cycloalkyl andcycloalkenyllower alkanoic acids [e.g., cyclohexaneacetic,a-cyclopentanebutyric, 2-cyclopenteneacetic and 3-(3-cyclohexene)pentenoic acids], and the like.

The term alkenyl includes mono-unsaturated straight chain or branchedchain radicals of less than eight carbons corresponding to lower alkylas defined above.

Examples of NRR" amino groups include monoor dilower alkyl-, arylalkyl-,lower alkylaryl-, alkenylor arylamino wherein lower alkyl and aryl areas defined herein, such as methylamino, ethylamino, isopropylamino,heptylamino, dimethylamino, diethylamino, ethylmethylamino,butylmethylamino, ethyl ipropylamino, allylamino, aniline, benzylamino,diphenylamino, naphthylamino, of N-methyl-N-phenylamino and the like.

NRR can be taken together to form a heterocyclic radical having theformula in which X represents NR", 0, S or CH r represents 1, 2 or 3;R'" represents hydrogen, lower alkyl, hydroxy-lower alkyl, loweralkanoyloxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, di( loweralkyl)aminolower alkoxy-lower alkyl, lower alkylamino-lower alkyl,di-lower alkyl amino-lower alkyl, amino-lower alkyl; and R" representsany of the R" groups. These may be exemplified by piperidinyl; (loweralkyl)piperidinyl [e.g., 2-, 3- or 4-(lower alkyl)piperidinyl]; (loweralkoxy )piperidinyl; pyrrolidinyl; (lower alkyl pyrrolidinyl', (loweralkoxy)pyrrolidinyl; piperazinyl', (lower alkyl)piperazinyl (e.g., N-methylpiperazinyl); di(lower alkylJpiperazinyl; (loweralkoxyJpiperazinyl; (hydroxylower alkyl)piperazinyl [e.g., N-(2-hydroxyethyl)piperazinyl]; (lower alkanoyloxyalkyl)piperazinyl [e.g.,N 2-acetoxyethyl )-piperazinyl (hydroxylower alkoxy-loweralkyl)piperazinyl [e.g., N*-[2-(2- hydroxyethoxy )ethyl lpiperazinyldi-( lower alkyl- )amino-( lower alkoxy-lower alkyl )piperazinyl [e.g.,N 2-( Z-dimethylaminoethoxy )ethyl ]piperazinyl homopiperazinyl; amino(lower alkyl)piperidinyl [e.g., 3-( aminomethyl)piperidinyl], loweralkylamino (lower alkyl )piperdinyl[piperidinyl[e.g., 2-[( methylamino)ethyl]piperidinyl], di-lower alkylaminoflower alkyl) piperidinyl[e.g.,4[ (dimethylamino)methyl ]piperidinyl].

The term amidd as employed herein includes radicals of the structurewherein R" can be lower alkyl, alkenyl, or aryl, substituted alkyl orsubstituted aryl, substituted with halogen, hydroxyl, alkoxy, amino ormonoor disubstituted amino or a monocyclic heterocycle such as pyridyLfury, thiazolyl, thienyl or pyrryl. The disubstituted amino substituent ofthe alkyl may also form a 5 to 7 membered heterocycle which may have upto two hetero atoms, such morpholino, pyrrolidino or pipcridino.

The term amino-substituted amido" includes radicals of the structurewherein n is l to [2 and (CH- represent alkylene chains, that is,bivalent saturated straight or branched aliphatic groups, containing lto 12 carbons, corresponding to the above-mentioned lower alkyl groupsand which may include lower alkyl and/or aryl side chains. Examples ofsuch alkylene groups include methylene, ethylene, l -methylethylene, 2-methylethylene, tetramethylene, propylene, trimethylene, hexamethylene,octamethylene, decamethylene. dodecamethylene, 3-methyldodecamethylene,dimethylethylene, l-phenylethylene and the like.

The salts of the compounds of this invention include the acid-additionsalts, particularly the non-toxic acid addition salts. Acids useful forpreparing the acidaddition salts, include inter alia, inorganic acids,such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid),sulfuric acid, nitric acid and phosphoric acid, and organic acids, suchas oxalic, maleic, fumaric, tartaric, citric, pamoic. acetic, andsuccinic acid.

Compounds of formula I wherein R and R are taken together to form =0that is can be prepared by reacting a naphthostyril derivative of thestructure can be prepared by reducing compound V above by reacting itwith an alkali metal borohydride, such as NaBH KBH, or LiBH Compounds offormula I wherein R is halogen and R" is hydrogen, that is 3 R :2 a N 0Hal can be prepared by reacting compound Vll above with a halogenatingagent such as thionyl chloride, thionyl bromide, phosphorus trichlorideor phosphorus tribromide.

Compounds of formula 1 wherein R is substituted amino (R R"N) and R" ishydrogen, that is can be prepared by reacting compound Vlll above withan amine of the structure R 2 a N o ethyl-Q can be prepared by refluxingcompound Vlll above with a lower alkanol.

Compounds of formula I wherein R is substituted amido, that is can beprepared by reacting compound Vll above with a nitrile of the structureXlll RCN 5 in the presence of an acid, in a Ritter reaction wherein R"is as defined hereinbefore.

Some specific examples of nitriles which are useful in the presentinvention are the following:

HC'N CH1; i CHOCH2CH2CN ('H cH cN CH,=(H('N CH, HOCH. .CH. .(N NCH2CH2CNCICHZCHJJN CH,,CH.

NCH2CHECN 0 N CH,CH.,CN (H;,CH

CH O- (N CH=CHCN 2% CH,. (N CH/N @VCN -(H2CN O N@' CH CN CH:! 0 cH,cNNCHi CN cnfl 40 I N cH. ,cN Olcmcn OCH2CH2CN c| (N The reaction betweenthe nitrile and compound VII conveniently takes place at about roomtemperature and at about atmospheric pressure. Operable tempera tures,however, may vary from about 20C to about 80C, preferably from about 0Cto about 60C and most preferably from about 25C to about 50C. Operablepressures may vary from about 0.2 atmosphere to about 5 atmospheres,preferably fr0m about 0.5 atmosphere to about 2 atmospheres, and mostpreferably at about atmospheric pressure. The reaction time may varyfrom a few minutes to several days. Generally, reaction times will befrom about 10 minutes to about I00 hours. Lower temperatures usuallyrequire longer reaction time.

While an excess of the nitrile is permissible, the nitrile and compoundVII may also be employed in stoichiometric quantities, or with a slightexcess of nitrile.

In the case of nitrilcs which are solid at room temperaturc, thereaction is preferably carried out in the presence of polar andnon-polar solvents such as, for examthat is 7 a n a N-(CH wherein n is lto 4, can be prepared by reacting compound XIl wherein R is (CH ),,l-lalthat is with an amine of the structure X.

Compounds of formula I wherein R is acyloxy or aroyloxy and R is H, thatis can be prepared by reacting compound V1] with a carboxylic acidcontaining up to twelve carbons or an acid anhydride thereof or aeyl oraroyl halide. Examples of such acids are set out hereinbcfore.

Examples of starting naphthostyril derivatives which can be employedherein include, but are not limited to, the following set out in Table Abelow:

TABLE A TABLE A Continued R R R" R X (position) Y (position) Q l. H H HH H B1 (4) C-IHA 2. H CH H H H F (4) CH3 4. CH, CH, CH (H H OCH (4; C,,H

8. H H CH, CH;, H I (5) H 9. (,H,, H H H OCH, (5) CH, m. (,H, H H H Br(m H c ,H,, l l. H H H H F (a) H c,,H,, l2. H H C,H H l (a) H H I]. (H,,H H CH, Cl 6 H H l4. CH CH. CH, c .,H OCH, (6) H H l5. c,,H,,, CH,, H Hc,,H (m H (,H, In. H CH; C.H,, H F (X) H H l7. H Ch H H CWHAHQ H CH"ltl. H, (.H, H CH, CH, (a) H H w. H H H C on H (,H,

Other examples of naphthostyril derivative starting EXAMPLE 1 materialsare set out in copending U.S. application Ser. No. 185,820, filed Oct.1, 1971 entitled Naphlhosryril Derivatives; and now abandoned.

Examples of other starting reactants such as R R NH, are set out in theworking Examples.

The compounds of this invention possess central nervous system modifyingactivity, particularly as depressants and are therefore useful astranquilizers. They may be administered orally or parenterally in theform of tablets, capsules, elixirs, injcctables or the like byincorporating the appropriate dosage of the compound with carriersaccording to accepted pharmaceutical practice.

The dosage for various mammalian species would be from 25 to 250 mg.administered orally or parenterally once to several times daily,dependent upon the individual requirements of the recipient.

In addition, the compounds of the invention have been found to inhibitcyclic AMP phosphodiesterase, thereby providing an increase in theintracellular concentration of aden0sine-3',5'-cyclic monophosphate. Theadministration of about 10 to 900 mg/kg/day, preferably about to 250mg/kg, of the compounds of the invention in single or two to fourdivided doses in conventional oral or parenteral dosage forms such asthose described above may be used to alleviate the symptoms of asthma.

Further, the compounds of the invention are useful sunsereening agents.

The compounds of this invention are also useful as anti-inflammatoryagents in warm blooded animals in a manner similar to indomethacin. Theymay be used to decrease joint swelling tenderness, pain and stiffness,in mammalian species, e.g., in conditions such as rheumatoid arthritis.A compound of formula 1 or a physiologically acceptable salt (whenapplicable) of the character described above may be compounded accordingto accepted pharmaceutical practice in oral dosage forms such astablets, capsules, elixirs or powders for administration of about 100 mgto 2 gm per day, preferably IOO mg to 1 gm per day in two to fourdivided doses.

The following examples illustrate the present invention without,however, limiting the same thereto. All temperatures are expressed in C.

2,3-Dihydroisoindolo[7,l,2-hij]quinoline-1,5-dione A mixture of 260 mgof 1,2-dihydro-2-oxobenz[cd]- indole-l-propionic acid in 12.5 ml ofpolyphosphoric acid is stirred and heated at for 1 hour. The mixture ispoured into water, stirred and extracted with chloroform. The chloroformextracts are washed with saturated sodium bicarbonate solution, 8% saltsolution, dried and evaporated. Plate chromatography of the residue onneutral alumina using chloroform as the developing solvent gives a majoryellow band which is eluted with ethyl acetate. Evaporation gives aresidue which is crystallized from ehloroform-isopropyl ether to give 117 mg of the title compound, m.p. 187l88. Recrystallization from thesame solvents gives the analytical sample, m.p. l87.5-l88.5.

Anal. Calcd. for C H.,,NO C, 75.32; H, 4.06; N, 6.28. Found: C, 75.21;H, 4.32, N, 6.14.

EXAMPLE 2 Q-Chloro-2,3-dihydroisoindolo[7,1,2-hij1quinoline- 1 ,S-dioneFollowing the procedure of Example 1, but employing 6-chlorol,2-dihydro-2-oxobenz[cd]indolel propionic acid as the starting material,there is obtained the title compound, m.p. 255.5256.5.

Anal. Calcd. for C l-l ClNO z Q6525; H.313; N544; Cl,l3.75. Found:C,65.27; H,3.40; N,5.l7; Cl,l4.()0.

EXAMPLE 3 2,3-Dihydrol -hydroxyisoindolo[ 7, l ,Z-hij lquinolin- 5( l H)-one A solution of l 17 mg of 2,3-dihydroixoindolol7,l.2-hij]quinoline-l,5-'dione in 5 ml of dioxanc and 5 ml of methanol istreated with 30 mg of sodium borohydride and stirred at room temperaturefor 1 hour. The mixture is concentrated, diluted with water andextracted with chloroform. The extracts are washed with 8% saltsolution, dried and evaporated. Plate chromatography of the residue onsilica gel using chloroform-ethyl acetate as the developing solventgives a major yellow band which is eluted with ethyl acetate.Evaporation gives a residue which is crystallized fromchloroformisopropyl ether to give 90 mg of the title compound, m.p.l62-l 63.5. Recrystallization from the same solvents gives theanalytical sample. m.p. l63-l64.

Anal. Calc'd. for C H NO C.74.65; H,4.92; N622. Found: C,74.55; H,5.l8'.N,6.2l.

EXAMPLE 4 9-Chloro-2.3-dihydrol -hydroxyisoindolo[ 7, l ,2-hij]quinoline-5( lH)-one Following the procedure of Example 3, butemploying 9-chloro-2,3-dihydroisoindolo[ 7. l ,2-hij]quinoline-1.5-dione as the starting material, there is obtained the titlecompound, m.p. 240.5-24l.5.

Anal. Calcd. for C H ClNO C, 64.75; H,3.88; N,5.40; Cl,l3.65. Found:C,64.54; H.407; N,5.l9; Cl.13.88.

EXAMPLES l-Acetoxy-2.3-dihydroisoindolo[7,1,2-hij]quinolin- 5(lH)-one Amixture of 200 mg of 2.3-dihydro-l- Anal. Cald'd. for C ,.H NO C,7l.90;H.490; N.5.l3. Found: C,7l.6l; H,5.08; N,5.24.

EXAMPLE6 l-Chloro-2,3-dihydroisoindolo[ 7, l ,Z-hij ]quinolin- 5(lH)-oneA mixture of [.0 g of 2,3-dihydro-lhydroxyisoindolo[7, l ,2-hij]quinolin-5( lH )-one in ml of benzene is treated with l.4 ml of thionylchloride and stirred overnight. The mixture is diluted with water andthe benzene layer separated. The benzene fraction is washed with water.8% salt solution. dried and evaporated to give the title compound.

EXAMPLE 7 l-Ethoxy-2,3-dihydroisoindolo[ 7. l ,Z-hij ]quinolin- 5(lH)-one A mixture of L66 g of l-ehloro-2,3-

EXAMPLE 8 2,3-Dihydro-l-morpholinoisoindolo[7,1,2- hij]quinolin-S(lHl-one A mixture of 1.66 g of l-chloro-2,3- dihydroisoindolo[7,l,2-hij]quinolin-5( lH)-one in 5 ml of morpholine and 25 ml of dioxane isrefluxed overnight. The mixture is evaporated, treated with 2N HCl andextracted with chloroform. The acid solution is made alkaline withsodium hydroxide and. extracted with chloroform. The chloroform extractsare washed with 8% salt solution, dried and evaporated. The residue iscrystallized from chloroformisopropyl ether to give 1.34 g of the titlecompound, m.p. l72l73.

Anal. Calcd. for C H N- O C,73.45; H,6.l6; N952. Found: C,73.2l; H,6.07;N,9.49.

EXAMPLE 9 2,3-Dihydrol -pyrrolidinoisoindolo[ 7, l ,2- hij]quinolin5(lH)-one, hydrochloride Following the procedure of Example 8, butemploying pyrrolidine as the amine, and converting the product to thehydrochloride salt, there is obtained the title compound, m.p. 292293d.

Anal. Calc'd. for CIBH QClN O: C,68.68; H,6.08; N,8.90; Cl,l 1.26.Found: C,68.52; H.631; N,8.65; Cl,] 1.52.

EXAMPLE 10 l-( Dimethylamino )-2,3-dihydroisoindolo[ 7, l ,2-hij]quinolin5( lH)-one, hydrochloride Following the procedure of Example9. but employing diethylamine as the amine, there is obtained the titlecompound. mp. 23 l .5232.5.

Anal. Caldd. for C,,.H .ClN O: Q6824; H.668; N,8.85; Cl.l 1. l9. Found:C.67.90; H.674; N9. l5; (Cl. 1 1.23.

EXAMPLE I l l ,9-Dichloro-2,3-dihydroisoindolo[ 7, l ,2- hij lquinolin5(lHl-one A solution of 500 mg of2.3-dihydro-lhydroxyisoindolol7,l,2-hij]quinolin-5( lHJ-one in 5 ml ofacetic acid is cooled in an ice-bath and treated with 0.25 ml ofsull'uryl chloride. After 30 minutes at room temperature. an additional0.25 ml of sulfuryl chloride is added and the mixture is stirred for 1.5hour. The mixture is diluted with water and extracted with chloroform.The chloroform extracts are washed with 87: salt solution. dried andevaporated. Plate chromatography of the residue on silica gel usingchloroform as the developing solvent gives a major yellow band which iseluted with ethyl acetate. Evaporation gives a residue which iscrystallized from acetone-petroleum ether to afford mg of the titlecompound, m.p. l27l29. Recrystallization from the same solvents providesthe analytical sample, m.p. l28l29.

Anal. Caldd. for C H Cl NO: C,60.47; H,3.23; N 5.04; 0.25.50 Found:C,6().77; H.351; N.4.98; 0.25.62.

EXAMPLE l2 9-Chloro-l3-dihydrol-pyrrolidinoisoindolol 7, l .2- hij]-quinolin-5( l H )-one, hydrochloride A mixture of 3.] g ofl,9-dichloro-2,3- dihydroisoindolo[7,1,2-hij]quinolin-5( lH)-one in 50ml ofdioxane and I0 ml ofpyrrolidine is refluxed overnight andevaporated. The residue is treated with 2N sodium hydroxide solution andextracted with chloroform. The chloroform extracts are washed with 8%salt solution, treated with charcoal. filtered and dried. The free baseis dissolved in dimethoxyethane treated with methanolic HCl and thesolid collected by filtration to afford 1.53 g of the title compound,m.p. 3()83U9d. Recrystallization from ethanol provides the analyticalsample, m.p. 3 l 23 l 4d.

Anal. Calcd. for C H Cl- N O: C,6l.9()l H.519; N,8.02; Cl,20.34. Found:C,6Z.l8; H,5.36; N,7.87; (120.54.

EXAMPLE 13 9-Chloro-2,3-dihydrol -morpholinoisoindolo[ 7, l ,2- hij]quinolin-( 1H l-one. hydrochloride Following the procedure of Example12, but employing morpholine as the base, there is obtained the titlecompound, m.p. 277279d,

Anal. Caled. for C,, H,,,Cl N O C,59.l8; H,4.97;

N,7.66; Cl,l9.l4. Found: C,59.01; H521; N,7.37; Cl,19.25.

EXAMPLE 14 l-Acrylamido-2,3-dihydroisoindolo[ '7, l ,Z-hij ]quinolin-5(lH)-one An ice-bath cooled suspension of 500 mg of 2,3- dihydro-1-hydroxyisoindolo[ 7, l ,Z-hijlquinolin- 5( lH)-one in 5 ml ofacrylonitrile is treated dropwise with 1.5 ml of concentrated sulfuricacid. The reaction mixture is stirred at room temperature for 2.5 hours,diluted with water and extracted with chloroform. The chloroformextracts are washed with 8% salt solution, dried and evaporated.Crystallization from chloroform gives 442 mg of the title compound, m.p.234235. Plate chromatography of this material on silica gel usingchloroform-ethyl acetate l :1 as the developing solvent gives a majoryellow band, which is eluted with ethyl acetate. Evaporation andcrystallization of the residue from chloroform gives the analyticalsample, m.p. 237238.

Anal. Calcd. for C H N O C,73.36; H.507; N,l0.07. Found: C,73.3l;H,4.98; N,l().()3.

EXAMPLE l5 l-Acetamido-2,3-dihydroisoindolo[ 7, l ,2-hij lquinoliin 5( lH )-one Following the procedure of Example 14, but employingacetonitrile, there is obtained the title compound, m.p. 253254.

Anal. Calcd. for C H N O- C,72.l6; H.530; N,1().52. Found: C,7l.89;H558; N,l0.43.

EXAMPLE l6 l-Benzamido-2,3-dihydroisoindolo[ 7. l ,Z-hij lquinolin- 5( lH )-one Following the procedure of Example 14, but employingbenzonitrilc, there is obtained the title compound, m.p. 26l.5262.5.

Anal. Calcd. for C H N O C,76.8l; H.491; N,8.53. Found: C,76.76; H,4.95;M846.

EXAMPLE 17 l-( 3-Bromopropionamido)-2,3- dihydroisoindolo[ 7, l ,Z-hij]-quinolin-5( 1H )-one 5 Following the procedure of Example 14, butemploying 3-hromopropionitrile, there is obtained the title compound,m.p. 2192 l9.5.

Anal. Calcd. for C, H, BrN O :.C,56.8S; H,4.2l; N,7.8(); Br,22.25.Found: C,57.10; H,4.34; N,7.73;

EXAMPLE l8 2,3-Dihydrol 3-morpholinopropionamidoisoindolo[7,1,2-hij]-quinolin-5( 1H )-one EXAMPLE 1'? 2,3-Dihydrol [3-(lpyrrolidinyl )propionamido]isoindolo[ 7, l ,2- hij]quinolin- 5( 1H)-one Following the procedure of Example 18, but employing pyrrolidineas the amine, there is obtained the title compound, m.p. 2l42 Anal.Calc'd. for C- H N O C,72.l8: H,6.63; N,l2.()3. Found: C,72.34; H,6.88:N,12.()7.

EXAMPLE l-[3-( Dicthylamino )propionamido]-2,3- dihydroisoindolo[7, l,2-hij]-quinolin-5( lH)-one, hydrochloride Following the procedure ofExample 18, but employing diethylamine as the amine and converting theproduct to its hydrochloride salt, there is obtained the title compound,m.p. 238239.

Anal. Calcd. for C H ,,ClN,-,O C,65.08; H.675; N.l().83; Cl,9.l4. Found:C,64.86; H,7.02; N,l 1.08; (1.9.08.

EXAMPLES 21 to 30 Following the procedure of Example 1, but employingthe naphthostyril derivative shown in column 1 of Table l in place ofl,Z-dihydro-i'Z-oxobenz-[cdl-indolel-propionic acid, the product shownin column 2 is obtained.

TABLE I TABLE Ill Columnl RI RI QOOCJ N I Example No. Hal R' R2 R" R' XY Example No. Q R R R R x Y 4] C] CH; H H H H H 42 Br c.,H H H c H 9-BrH 31 H H E 2' 3 43 c1 C CH" CH CH" H 7 0cH,., '1 H H 44 Br c,.H, cH CH,CH" '-)CH, H 33 E H 4-00 45 Cl H H C H H 7N(CHY,, 3 C CH: CH CIHT CH36CH.-, H 46 C] H H H H H S OCHJ' "l H H H H FMCHW 47 Br C2H5 CH (7 H,CH1, H 7Br 26 H H H H H S-OCHH 48 G H H CH" H H 27 CH" .H CH1 c H 0H,, H4-Br 49 Br CH1 CH1 H H 9 OCH H 28 H H H CH1, H H 5F 50 H H 9F H 29 CH1,cH,. CH H H 6OCH;, H 30 H H H H H 6-F H EXAMPLES 5| TO 60 Following theprocedure of Example 5, but substitut- Following the procedure ofExample 3, but substituting the ketones prepared in Examples 2| to forthe ketone used in Example 3, the hydroxy compound EXAMPLES To 40 ingthe l-hydroxy compound prepared in Example 3l to 40 and the acid, acidanhydride, or acyl or aroyl halide shown in column I of Table IV below,the product shown in column 2 is obtained t 30 shown In Table ll belowlb obtalnedt TABLE IV TABLE ll Product 1 R O 5 ll R -C-O 40 AcidAnhydride Example or Acid or Aruyl No. or Acyl Halide Example 2 71 I N0.R R R R X Y c LIC- RIICOOH 0 3| CH H H H H H 32 z r. H H C2:- H or RCHal33 CH CH CH CH" H 1 R-'- R R R x Y R 34 (3H, CH,, H CH 9 C,,H H 35 H HCH, H H (C' =l); q I 36 H H Ha I H H 8 OCHH (3H1 (:H, H H H H H 7 C CHCH H 7 B -H,-, (2H -,H H CHHfJ-Br H As per C .H,-, H 2 5 4| T 53 H,,CH5, CH1, CH3 CH3 H 7CH;|O Column I 33 H H CH H H 8-F 29 CH H H 9 H 54 rlrl a": H II T CH3 u s H CH3 :x 1| S5 H -,(H. H H (KHHH H 7(CH;,)2N 40 HH H H H 56 C H H H H H K-OCH,

57 CH C.,H,, CH c ,H ,CH H 7Br 58 (.H,-, H H CH;I H H 8F 6U EXAMPLES 41TO 50 59 D CH H HOCHH Following the procedure of Example 6, butsubstitutin for the 2.3-dih dro-l-h drox isoi )lo 7 y y y no OCH: H H HH u-F H h\ ]qumohn5( lH)-0ne, the compounds prepared In Examples 31 to40, the product shown below in Table III is obtained. Example No.

EXAMPLES 6| TO 70 EXAMPLES 71 TO 80 Following the procedure of Example8, but substituting the halonaphthostyril starting material prepared inExamples 4| to 50 and the amine or heterocyclic reactant shown in Columnl of Table VI below, the product shown in Column 2 is obtained.

wherein n is l to 4 as per the procedure of Examples [4 and 81 to 90)and the amine shown in column 2, the product shown in column 3 isobtained,

EXAMPLES 8| TO 90 Following the procedure of Example l4. butsubstituting the 2.3-dihydrol -hydrox visoindolo[ 7. l .2- hij]Luinlin-5( lHJ-onc compounds of Examples 3l to 40 and the nitrile shownin column 1 of Table V", the product shown in column 2 is obtained.TABLE VI" Column 1 TABLE VII R 2 1$ N 9 4 R -c NH Y 15 Example No. R"CNRU Rll R! R2 R1] R-I X Y 8l C;,H7 C3H; CH3 H H H H 82 s I s (7 H, H H(3H,, 9Br H 83 p OCH C H pOCH C H CH CH CH CH H 7CH O s4 -C1 C H, p ClCH, C H 7 CH C,.HT CH1. Qi H 85 pOHC H, p-OH-CJL- H H (1H,, H H 7(CH;,),N86 p-(C H l\lC, H p-(C H NC H,, H H H H H 8-OCH;, 87 Cu c CH C,H CH H7Br as CICH,CH C|cH .CH., H H CH H H 8F CH,, CH 89 NCH cH NCHZCH, CH"CH, H H 9-OCH H 90 N-CHgCN NCH2CN H H H H 9F H EXAMPLES 9| to I00 Column3 Following the procedure of Example [8, but substituting as startingmaterials the halogen-napthostyril de- 2 R 4 rivatives shown in column Iof Table Vlll below (pre- R R pared by reacting any of the compounds ofExamples 0 3, 4 and 31-40 with a nitrile th r of e st ucture 7 8 2 n YHal-(CH ),,CN

HNRTR" Ex No. Hul n R' R R"I R X Y RTR"N n R R2 R" R X Y 9] Cl l CH1| HH H H H HN(C.,H,-,)CH;, As per As per Column 1 Column )2 Br 2 (!H,-, H HC- ,H 9,Br H HN 2 93 Br 1 (H (H. CH, CH H 7CH;,O HN S 94 (I 4 H- CH H-CH JC.;H H HI\' I I I H H (.H H H 7(('H;,)2N HN ((HMEOH an Br .1 H H H HH fi OCH HNHCH,

l. The compound having the name l-acrylamido-l What is claimed is:

dihydroisoindolo{ 7. l ,Z-hij ]quinolin-5( lH )-nc.

dihydroisoindolol 7, l ,2-hij ]quinoiin-( l H )-onc.

3. The compound having the name l-bcnzumido-2,3-

dihydroisoindolo[ 7. l ,Z-hij ]quinolin-5( l H )-one.

morpholinopropionumido )-is0ind0lo[7, l ,2- hij ]quin0Iin-5( l H )-onc.

6. The compound having the name 2,3-dihydro-I-[3- pyrrolidinyl)propionumidolisoindoloE7,1.2-hij]quinolin-S( 1H )-one.

7. The compound having the name l-[3- (dicthylumino )pr0pionamid0]-2,3-

4. The compound having the name 1-(3- hromopropionumido )-23-dihydr0is0indol[7, l ,2- yqzj kfl 7, i .2-h1 ]qum0l|n-5( l H )-one,hydrohij]quinolin-5(1H)one.

S.Thc compound having the name 2,3-dihydro-l-(3- UNITED STATES PATENTAND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,910,923DATED October 7, 1975 INVENTOR(S) Seymour D. Levine it is certified thatmm appears in the ab0veidenhfied patent and that said Letters Patent arehereby correcied as shown bBIP-WI Column 1, line 7, the formula shouldhave I before it. Column 2, line 25, the formula should have II beforeit. Column 2, line 61, the formula should have III before it. Column 3,line 10, the formula should have IV before it. Column 3, line 35, theformula should have V before it. Column 3, line 46, the formula shouldhave VI before it. Column 3, line 65, the formula should have VII beforeit. Column 4, line 6, the formula should have VIII before it. Column 4,line 22, the formula should have IX before it. Column 4, line 35, theformula should have X before it. Column 4, line 45, the formula shouldhave XI before it. Column 4, line 60, the formula should have XII beforeit.

Column 6, line 16, the formula should have XIV before it. Column 6, line30, the formula should have XV before it. Column 6, line 41, the formulashould have XVI before it. Column 12, line 56 should read Table I---.

Column 12, line 57 should read -Column II.

Column 12, line 66, afterthe formula should read:

As per Column I Column 13, line 1, omit "Table I". Column 15, line 80,there should be a before the first N in the second column.

Column 19, line 26, "dihydroisoindol" should read dihydroisoindolo-.

Signed and Scaled this A rres t.

RUTH C. MASON Arresting ()f C MARSHALL DANN wmlsswm r of Iarenls andTrademarks

1. THE COMPOUND HAVING THE NAME 1ACRYLAMIDO-2.3-DIHYDROISOINDOLO(7.1.2-HIJ)QUINOLIN-5(IH)-ONE.
 2. Thecompound having the name 1-acetamido-2,3-dihydroisoindolo(7,1,2-hij)quinolin-5(1H)-one.
 3. The compound having the name1-benzamido-2,3-dihydroisoindolo(7,1,2-hij) quinolin-5(1H)-one.
 4. Thecompound having the name 1-(3-bromopropionamido)-2,3-dihydroisoindol(7,1,2-hij)quinolin-5(1H)-one.
 5. The compound having the name2,3-dihydro-1-(3-morpholinopropionamido)-isoindolo(7,1,2-hij)quinolin-5(1H)-one.
 6. The compound having the name2,3-dihydro-1-(3-(1-pyrrolidinyl)propionamido)isoindolo(7,1,2-hij)quinolin-5(1H)-one.
 7. The compound having the name1-(3-(diethylamino)propionamido)-2,3-dihydroisoindolo(7,1,2-hij)quinolin-5(1H)-one, hydrochloride.